Abstract: The present invention encompasses engineered meganucleases that bind and cleave a recognition sequence within a TTR gene. The present invention also encompasses methods of using such engineered meganucleases to make genetically-modified cells. Further, the invention encompasses pharmaceutical compositions comprising engineered meganuclease proteins, or nucleic acids encoding engineered meganucleases of the invention, and the use of such compositions for treatment of TTR-associated diseases, such as transthyretin amyloidosis.

Abstract: Disclosed herein are engineered nucleases that bind and cleave a recognition sequence within intron 1 of a transferrin gene, and methods of using such engineered nucleases to produce a genetically-modified eukaryotic cell comprising a modified transferrin gene. Further provided are pharmaceutical compositions and methods for treatment of a variety of conditions through expression of a polypeptide of interest encoded by an exogenous nucleic acid molecule inserted in intron 1 of a transferrin gene and expressed under the control of the endogenous transferrin promoter.